Enantioselective Synthesis of [3]-Ladderanol through a Late-Stage Organocatalytic Desymmetrization

Ladderane phospholipids, with their unusual ladder-like arrangement of fused cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise synthesis of [3]-ladderanol, a component of ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2)‒H alkylation. Our synthetic strategy rests on a late-stage introduction of chirality, thus allowing facile access to both the enantiomers of [3] ladderanol as well as its analog. This is the first time a desymmetrization strategy is applied to the synthesis of [3]-ladderanol. The scope of this desymmetrizing C(sp2)‒H alkylation of meso cyclobutane fused cyclohexenediones is also presented.